Orthopedic joint reconstruction with an implanted artificial prosthesis is an increasingly common surgical procedure. Unfortunately, at least 7% of patients receiving such prostheses will experience implant loosening and, ultimately, failure within 5-7 years of surgery. The precise reasons for this high rate of failure are unknown. However, histological studies of the tissues surrounding loosened implants suggests that mononuclear phagocytes (MO) and foreign body giant cells (GCs) play an important role in the rejection process. Specifically, these cells, which seem to be recruited by implant derived particles, are believed to be directly responsible for resorbing the bone immediately surrounding the implant, and are perhaps instrumental in the development of an inappropriately thick connective tissue capsule between the implant and the supporting tissue. However tenable is the hypothesis regarding the role of MOs and GCs in implant loosening, it is based upon histological observations and is therefore, at best, intuitive. The aim of the present proposal is to directly assess the potential of MOs and GCs to affect those changes believed essential to prosthetic loosening, particularly when exposed to implant derived materials. These studies will focus on use of in vitro assay systems, established in this laboratory, with which we have previously (a) documented the ability of MOs to resorb vital and devitalized bone, (b) demonstrated that bone matrix degradation can be precisely quantitated, and (c) shown that MO- and GC-mediated bone resorption can be regulated by systemic bone-seeking agents (e.g., cortisol) and by, as yet, undefined factors released by other cells. In this application, we propose to extend the use of these techniques and experience, to: (1) evaluate the action of implant materials on MO- and GC-mediated bone; (2) identify the enzyme(s) responsible for bone collagen degradation by MO and GC, and explore the regulation of this enzyme(s) by implant materials; (3) study the potential of MO, GCs and endothelial cells exposed to implant derived material to modulate (stimulate) bone resorption by other cells, including osteoclasts; and (4) establish whether phagocytosis of implant particles by MOs promotes the release of agents capable of stimulating giant cell formation and fibroblast proliferation.